Cyclodextrins (CD-s) and particularly their water-soluble derivatives increase the water-solubility of various drugs very significantly (in some cases by 2 to 3 orders of magnitude). Thus, their use is advantageous not only for enhancing the biological availability of orally administered drugs but also for improving the transdermal absorption of active agents and for the preparation of new "injectable" preparations.
However, in both of these latter fields of application essential requirements are a low level of local irritation and haemolytic activity. The haemolyzing effect of the various CD-s and their derivatives shows considerable differences. It is thus possible to prepare derivatives with an insignificant haemolyzing effect.
In low concentrations (5 mmol in the case of .alpha.-CD and 10 mmol in the case of .gamma.-CD, respectively), CD-s protect the human erythrocytes against heat-induced or osmotic haemolysis whereas at higher concentrations (3 mmol of .beta.-CD, 6 mmol of .alpha.-CD and 16 mmol of .gamma.-CD, at 37.degree. C. and pH 7,4 in 10 mmoles of an isotonic phosphate buffer), a haemolysis is induced. At these high concentrations, cholesterol is extracted from the cell membrane by CD-s (in an order of efficiency of .beta.&gt;.gamma.&gt;.alpha.), a fact indicating that the CD-induced haemolysis is a secondary phenomenon which is the consequence of an interaction between the CD-s and membrane components.
According to scanning electron microscope photographs, the protective action of CD-s below the critical concentrations mentioned above is due to the membrane expansion. It is likely that the fluidization of the membrane lipids is altered by CD-s whereby the erythrocytes are protected; however, these lipids are extracted from the membrane by higher CD concentrations, which lead to destruction of the membrane [J. Pharm. Dyn. 5, 741 (1982)].
In conclusion, it is desirable to prepare derivatives which make water-soluble various lipophilic active agents by complex formation, and react with the cell membrane lipids in such a way that their fluidity is decreased but that they are not extracted from the cell wall, i.e. the cell walls are not damaged and thus the erythrocytes are not haemolyzed.
Up to the present, four types of derivatives have been prepared for this purpose:
(a) Methylated CD-s, described abudantly in the literature are highly soluble and possess a high solution power (see German Patent No. 3,118,218), however their haemolytic effect is high (J. Szejtli: Cyclodextrin Technology, Ed. Reidel, Dordrecht, 1987).
(b) Acid-type ionic derivatives (carboxymethyl, sulfpropyl etc. compounds) have a lower haemolytic activity, but, their solution power is much weaker (J. Szejtli: Cyclodextrins and their Inclusion Complexes, Ed. Akademiai Kiado, Budapest, 1982).
(c) The heterogeneous hydrophilic derivatives, e.g. hydroxypropyl-CD (European Patent No. 149,197) or soluble ionic CD polymers (Hungarian Patent No. 191,101) are scarcely haemolytic, but their preparation in a pure state is problematic. A further problem is the fate of the polymer in the organism, which has not been cleared up. These heterogeneous derivatives are not crystallizable so that their preparation in a technologically pure form requires expensive operations.
(d) Ethylated or dialkylaminoethylated and mixed ether derivatives can be characterized only by an average degree of substitution and are inhomogeneous, crystallizable substances (European Patents Nos. 146,841 and 147,685).